Heteroaryl compounds as type ii irak inhibitors and uses thereof

ABSTRACT

The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof, useful as IRAK inhibitors.

TECHNICAL FIELD OF THE INVENTION

The present invention provides for compounds of Formula (I) as IRAKinhibitors and their use in the treatment of cancer, and other diseasesrelated to IRAK overexpression, including inflammatory disorders,autoimmune disorders, and cancer.

BACKGROUND OF THE INVENTION

Kinases catalyze the phosphorylation of proteins, lipids, sugars,nucleosides and other cellular metabolites and play key roles in allaspects of eukaryotic cell physiology. Especially, protein kinases andlipid kinases participate in the signaling events which control theactivation, growth, differentiation and survival of cells in response toextracellular mediators or stimuli such as growth factors, cytokines orchemokines. In general, protein kinases are classified in two groups,those that preferentially phosphorylate tyrosine residues and those thatpreferentially phosphorylate serine and/or threonine residues.

Kinases are important therapeutic targets for the development ofanti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology21, 1-8), for example kinases that are involved in the orchestration ofadaptive and innate immune responses. Kinase targets of particularinterest are members of the IRAK family.

IRAKs (IL-1 receptor associated kinases) are Ser/Thr kinases signalingdownstream of TNF-R, IL-1β-R, IL-18R and toll-like receptors. IRAKs inturn mediate JNK/p38 and NFκB activation, leading to pro-inflammatorycytokine production. From four family members only IRAK1 and 4 possesskinase activity, where IRAK4 acts upstream of IRAK1 within the samepathway. In myeloid cells IRAK1 is required for LPS-induced IL-8 andINF-γ release, STAT3 activation, IL10 release and β2-integrin-mediatedcell spreading. In pDC's, IRAK mediates TLR7 and 9-induced release ofINF-α. In T cells, IRAK mediates IL-2 production and proliferation, aswell as IL-18-induced Th1 cell proliferation and INF-γ production.Expression of IRAKs is particularly high in endothelium, epithelium,macrophages, monocytes, mast cells, granulocytes, dendritic cells, B, Tand NK cells. Mice deficient in IRAK-1 or 4 present impaired INF-αproduction in response to TLR7/9 activation, fail to activate NFκB inresponse to IL-18 or IL-1, present a drastic decrease in INF-γproduction by Th1 and NK cells. They are also protected in models ofLPS-induced cardiac failure, CIA, Carageenan, lung inflammation andfibrosis and MOG-induced EAE. IRAK1 phosphorylation is enhanced upon LPStreatment of synoviocytes from RA patients. SNP's in IRAK1 areassociated with SLE.

The interleukin-1 receptor-associated kinases (IRAKs) are criticallyinvolved in the regulation of intracellular signaling networkscontrolling inflammation (Ringwood and Li, 2008. Cytokine 42, 1-7).IRAKs are expressed in many cell types and can mediate signals fromvarious cell receptors including toll-like receptors (TLRs). IRAK4 isthought to be the initial protein kinase activated downstream of theinterleukin-1 (IL-1) receptor and all toll-like-receptors (TLRs) exceptTLR3, and initiates signaling in the innate immune system via the rapidactivation of IRAK1 and slower activation of IRAK2. IRAK1 was firstidentified through biochemical purification of the IL-1 dependent kinaseactivity that co-immunoprecipitates with the IL-1 type 1 receptor (Caoet al., 1996. Science 271(5252): 1128-31). IRAK2 was identified by thesearch of the human expressed sequence tag (EST) database for sequenceshomologous to IRAKI (Muzio et al., 1997. Science 278(5343): 1612-5).IRAK3 (also called IRAKM) was identified using a murine EST sequenceencoding a polypeptide with significant homology to IRAK1 to screen ahuman phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNAlibrary (Wesche et al., 1999. J. Biol. Chem. 274(27): 19403-10). IRAK4was identified by database searching for IRAK-like sequences and PCR ofa universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA99(8):5567-5572).

Mice that express a catalytically inactive mutant of IRAK4 instead ofthe wild-type kinase are completely resistant to septic shock triggeredby several TLR agonists and are impaired in their response to IL-1.Children who lack IRAK4 activity due to a genetic defect suffer fromrecurring infection by pyogenic bacteria. It appears that IRAK-dependentTLRs and IL-1Rs are vital for childhood immunity against some pyogenicbacteria but play a redundant role in protective immunity to mostinfections in adults. Therefore IRAK4 inhibitors may be useful for thetreatment of chronic inflammatory diseases in adults without making themtoo susceptible to bacterial and viral infections (Cohen, 2009. CurrentOpinion in Cell Biology 21, 1-8). Potent IRAK4 inhibitors have beendeveloped (Buckley et al., 2008. Bioorg Med Chem Lett. 18(12):3656-60).IRAK1 is essential for the TLR7-mediated and TLR9-mediated activation ofIRF7 and the production of interferon-alpha (IFN-α) suggesting thatIRAK1 inhibitors may be useful for the treatment of Systemic lupuserythematosus (SLE). IRAK2 is activated downstream of IRAK4 and plays arole in proinflammatory cytokine production. Therefore IRAK2 inhibitorsmay be useful for inflammatory diseases.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula (I):

and pharmaceutically acceptable derivatives, solvates, salts, hydratesand stereoisomers thereof, wherein each of A′, L, X, Y, Z, R¹, and R²,is as defined below and described in the embodiments.

In another aspect, the invention provides compounds of Formula (I) whichare suitable for the treatment and/or prevention of disorders related toIRAK. In another aspect, the invention provides compounds which are ableto modulate, especially inhibit the activity or function of IRAK indisease states in mammals, especially in humans.

According to another aspect of the invention are provided methods forthe treatment and/or prevention of disorders selected from auto-immune,inflammatory disorders, cardiovascular diseases, neurodegenerativedisorders, bacterial and viral infections, allergy, asthma,pancreatitis, multi-organ failure, kidney diseases, plateletaggregation, cancer, transplantation, sperm motility, erythrocytedeficiency, graft rejection, lung injuries, respiratory diseases,ischemic conditions, and cancer.

According to another aspect, the present invention provides compounds ofFormula (I) which are selective for IRAK-4 and/or IRAK-1, with type IImode of binding.

According to another aspect, the present invention provides compounds ofFormula (I) which are selective for IRAK-4 and IRAK-1, with type II modeof binding.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain aspects, the present invention provides for inhibitors ofIRAK. In some embodiments, such compounds include those of the formulaedescribed herein, or a pharmaceutically acceptable salt thereof, whereineach variable is as defined and described herein.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Exemplary aliphatic groups are linear or branched, substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, C₁, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. The term “aryl”is used interchangeably with the term “aryl ring”. In certainembodiments of the present invention, “aryl” refers to an aromatic ringsystem. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyland the like, which optionally includes one or more substituents. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group is optionally mono- or bicyclic. The term “heteroaryl”is used interchangeably with the terms “heteroaryl ring”, “heteroarylgroup”, or “heteroaromatic”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5-to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl),or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic.The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, certain compounds of the invention contain“optionally substituted” moieties. In general, the term “substituted”,whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure (e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group has asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure is substituted withmore than one substituent selected from a specified group, thesubstituent is either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable”, as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently deuterium; halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄ Ph, which areoptionally substituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which isoptionally substituted with R^(∘); —CH═CHPh, which is optionallysubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which is optionallysubstituted with R^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂;—(CH₂)₀₋₄N(R^(∘))C(O)R^(∘); —N(R^(∘))C(S)R^(∘);—(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂;—(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘))₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), SC(S) SR^(∘), —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘))₂; —C(S)NR^(∘))₂; —C(S) SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘))₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘),—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄₀ S(O)₂R^(∘);—S(O)₂NR^(∘))₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) is optionallysubstituted as defined below and is independently hydrogen, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which is optionally substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently deuterium, halogen, —(CH₂)₀₋₂R^(●),-(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂R^(●), —(CH₂)₀₋₂CH(OR^(●))₂;—O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂ SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●), —OSiR^(●) ₃,—C(O)SR^(●), —(C₁₋₄ straight or branched alkylene)C(O)OR^(●), or—SSR^(●) wherein each R^(●) is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(∘) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*2))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which is substituted as defined below, oran unsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*2)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which is optionally substitutedas defined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which is optionallysubstituted as defined below, unsubstituted —OPh, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of Rt,taken together with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, the terms “optionally substituted”, “optionallysubstituted alkyl,” “optionally substituted “optionally substitutedalkenyl,” “optionally substituted alkynyl”, “optionally substitutedcarbocyclic,” “optionally substituted aryl”, “optionally substitutedheteroaryl,” “optionally substituted heterocyclic,” and any otheroptionally substituted group as used herein, refer to groups that aresubstituted or unsubstituted by independent replacement of one, two, orthree or more of the hydrogen atoms thereon with typical substituentsincluding, but not limited to:

—F, —Cl, —Br, —I, deuterium,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH— aryl, —NH -heteroaryl, —NH -heterocyclic,-dialkylamino, -diarylamino, -diheteroarylamino,

—O— alkyl, —O— alkenyl, —O— alkynyl, —O— cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocyclic,

—C(O)— alkyl, —C(O)— alkenyl, —C(O)— alkynyl, —C(O)— carbocyclyl,—C(O)-aryl, —C(O)— heteroaryl, —C(O)-heterocyclyl,

—CONH₂, —CONH— alkyl, —CONH— alkenyl, —CONH— alkynyl, —CONH-carbocyclyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclyl,

—OCO₂— alkyl, —OCO₂— alkenyl, —OCO₂— alkynyl, —OCO₂— carbocyclyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocyclyl, —OCONH₂, —OCONH—alkyl, —OCONH— alkenyl, —OCONH— alkynyl, —OCONH— carbocyclyl, —OCONH—aryl, —OCONH— heteroaryl, —OCONH— heterocyclyl,

—NHC(O)— alkyl, —NHC(O)— alkenyl, —NHC(O)— alkynyl, —NHC(O)—carbocyclyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl,—NHCO₂— alkyl, —NHCO₂— alkenyl, —NHCO₂— alkynyl, —NHCO₂-carbocyclyl,—NHCO₂— aryl, —NHCO₂— heteroaryl, —NHCO₂-heterocyclyl, —NHC(O)NH₂,—NHC(O)NH— alkyl, —NHC(O)NH— alkenyl, —NHC(O)NH— alkenyl, —NHC(O)NH—carbocyclyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH—heterocyclyl, NHC(S)NH₂, —NHC(S)NH— alkyl, —NHC(S)NH— alkenyl,—NHC(S)NH— alkynyl, —NHC(S)NH— carbocyclyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclyl, —NHC(NH)NH₂, —NHC(NH)NH—alkyl, —NHC(NH)NH— -alkenyl, —NHC(NH)NH— alkenyl, —NHC(NH)NH—carbocyclyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH—heterocyclyl, —NHC(NH)— alkyl, —NHC(NH)— alkenyl, —NHC(NH)— alkenyl,—NHC(NH)— carbocyclyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocyclyl,

—C(NH)NH— alkyl, —C(NH)NH— alkenyl, —C(NH)NH— alkynyl, —C(NH)NH—carbocyclyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclyl,

—S(O)— alkyl, —S(O)— alkenyl, —S(O)— alkynyl, —S(O)— carbocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclyl —SO₂NH₂, —SO₂NH— alkyl,—SO₂NH— alkenyl, —SO₂NH— alkynyl, —SO₂NH— carbocyclyl, —SO₂NH— aryl,—SO₂NH— heteroaryl, —SO₂NH— heterocyclyl,

—NHSO₂— alkyl, —NHSO₂— alkenyl, —NHSO₂— alkynyl, —NHSO₂— carbocyclyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocyclyl,

—CH₂NH₂, —CH₂SO₂CH₃,

-mono-, di-, or tri-alkyl silyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S— alkynyl, —S—carbocyclyl, —S-aryl, —S-heteroaryl, —S-heterocyclyl, ormethylthiomethyl.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. In some embodiments, the groupcomprises one or more deuterium atoms.

There is furthermore intended that a compound of the formula I includesisotope-labeled forms thereof. An isotope-labeled form of a compound ofthe formula I is identical to this compound apart from the fact that oneor more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phos-phorus,fluo-rine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. A compound of the formula I,a prodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labeled compound of the formula I can be used in a number ofbeneficial ways. For example, an isotope-labeled compound of the formulaI into which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated, is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labeled compound. Higher metabolic stability translates directlyinto an increased in vivo half-life or lower dosages, which under mostcircumstances would represent a preferred embodiment of the presentinvention. An isotope-labeled compound of the formula I can usually beprepared by carrying out the procedures disclosed in the synthesisschemes and the related description, in the example part and in thepreparation part in the present text, replacing a non-isotope-labeledreactant by a readily available isotope-labeled reactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus causes a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a com-poundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art is able to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favorable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favorable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

As used herein, the term “modulator” is defined as a compound that bindsto and/or inhibits the target with measurable affinity. In certainembodiments, a modulator has an IC₅₀ and/or binding constant of lessabout 50 μM, less than about 1 μM, less than about 500 nM, less thanabout 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in IRAK activity between a samplecomprising a compound of the present invention, or composition thereof,and IRAK, and an equivalent sample comprising IRAK, in the absence ofsaid compound, or composition thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

3. Description of Exemplary Compounds

According to one aspect, the present invention provides a compound offormula I,

-   or a pharmaceutically acceptable salt thereof, wherein:-   A′ is C═O, C(R)₂ or NR;-   L is a divalent group selected from C₃₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   X is CR or N;-   Y is NR or S;-   Z is CR or N;-   R¹ is C₃₋₁₀ aryl, a 3-8 membered saturated or partially unsaturated    carbocyclic ring, a 3-7 membered heterocylic ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; each of    which is optionally substituted;-   R² is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂;-   each R is independently hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; each of which is    optionally substituted; or-   two R groups on the same atom are taken together with the atom to    which they are attached to form a C₃₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, A′ is C═O. In certain embodiments, A′ is C(R)₂.In certain embodiments, A′ is NR.

In certain embodiments, A′ is C═O, CH₂, CHOH, or NH.

In certain embodiments, A′ is C═O. In certain embodiments, A′ is CH₂. Incertain embodiments, A′ is CHOH. In certain embodiments, A′ is NH.

In certain embodiments, L is a divalent optionally substituted C₃₋₁₀aryl. In certain embodiments, L is a divalent optionally substituted 3-8membered saturated or partially unsaturated carbocyclic ring. In certainembodiments, L is a divalent optionally substituted 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, L is a divalentoptionally substituted 5-6 membered monocyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, L is a divalent group selected from phenyl,naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl,[4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl,fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl,imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; -1,2,5oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl;each of which is optionally substituted.

In certain embodiments, L is a divalent group selected from phenyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, purinyl, pyranyl,pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, thiazolyl, thienyl, thiophenyl, oxetanyl,and azetidinyl, each of which is optionally substituted.

In certain embodiments, L is a divalent group selected from phenyl,cyclohexyl, and cyclohexenyl; each of which is optionally substituted.

In certain embodiments, L is a divalent group selected from

In certain embodiments, in the definitions of L provided above, eachgroup may face the direction as shown, or the reverse direction (e.g.,

represents both

In certain embodiments, X is CR. In certain embodiments, X is CH. Incertain embodiments, X is N.

In certain embodiments, Y is NR. In certain embodiments, Y is NMe. Incertain embodiments, Y is S.

In certain embodiments, Z is CR. In certain embodiments, Z is CH. Incertain embodiments, Z is N.

In certain embodiments, Z is N, Y is NR, and X is CR.

In certain embodiments, Z is N, Y is NR, and X is N.

In certain embodiments, Z is N, Y is S, and X is CR.

In certain embodiments, Z is CR, Y is NR, and X is N.

In certain embodiments, R¹ is C₃₋₁₀ aryl.

In certain embodiments, R¹ is

In certain embodiments, R² is C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R² is C₁₋₆ aliphatic.

In certain embodiments, R² is C₃₋₁₀ aryl.

In certain embodiments, R² is a 3-8 membered saturated or partiallyunsaturated carbocyclic ring.

In certain embodiments, R² is a 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R² is a 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur

In certain embodiments, R² is C₁₋₆ aliphatic or 3-7 membered heterocylicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, R² is methyl, ethyl, propyl, i-propyl, n-butyl,i-butyl, t-butyl, straight chain or branched pentyl, or straight chainor branched hexyl, or R² is a 4 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R² is —CF₃,

In certain embodiments, each of A′, L, X, Y, Z, R, R¹, and R², is asdefined above and described in embodiments, classes and subclasses aboveand herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-a,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y,R¹, and R² is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-b,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, R¹,and R² is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-c,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y,R¹, and R² is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-d,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, R¹,and R² is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-e,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y,Z, R¹, and R² is as defined above and described in embodiments, classesand subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-f,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y,R¹, and R² is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-g,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y,R¹, and R² is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-h,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, R¹,and R² is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-j,

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Z,R¹, and R² is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound selected fromTable 1:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

In some embodiments, the present invention provides a compound selectedfrom those depicted above, or a pharmaceutically acceptable saltthereof.

In certain embodiments, the compounds of the invention exhibit increasedmicrosome stability and permeability.

Various structural depictions may show a heteroatom without an attachedgroup, radical, charge, or counterion. Those of ordinary skill in theart are aware that such depictions are meant to indicate that theheteroatom is attached to hydrogen (e.g.,

is understood to be

In certain embodiments, the compounds of the invention were synthesizedin accordance with the schemes provided in the Examples below.

4. Uses, Formulation and Administration Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit IRAK, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, theamount of compound in compositions of this invention is such that iseffective to measurably inhibit IRAK, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition.

The term “patient” or “subject”, as used herein, means an animal,preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat are used in the compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

Compositions of the present invention are administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention include aqueous or oleaginous suspension.These suspensions are formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that are employed are water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium.

For this purpose, any bland fixed oil employed includes synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents that arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms arealso be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention are orallyadministered in any orally acceptable dosage form. Exemplary oral dosageforms are capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents are optionally also added.

Alternatively, pharmaceutically acceptable compositions of thisinvention are administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention are alsoadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches are also used.

For topical applications, provided pharmaceutically acceptablecompositions are formulated in a suitable ointment containing the activecomponent suspended or dissolved in one or more carriers. Exemplarycarriers for topical administration of compounds of this are mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, provided pharmaceutically acceptable compositions can beformulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Pharmaceutically acceptable compositions of this invention areoptionally administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that are optionallycombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, provided compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe compound can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

The present invention furthermore relates to a method for treating asubject suffering from an IRAK related disorder, comprisingadministering to said subject an effective amount of a compound offormula I and related formulae.

The present invention preferably relates to a method, wherein the IRAKassociated disorder is an autoimmune disorder or condition associatedwith an overactive immune response or cancer. The present inventionfurthermore relates to a method of treating a subject suffering from animmunoregulatory abnormality, comprising administering to said subject acompound of formula (I), and related formulae in an amount that iseffective for treating said immunoregulatory abnormality.

The present invention preferably relates to a method wherein theimmunoregulatory abnormality is an autoimmune or chronic inflammatorydisease selected from the group consisting of: allergic diseases,amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus,chronic rheumatoid arthritis, type I diabetes mellitus, inflammatorybowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn'sdisease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,autoimmune myositis, Wegener's granulomatosis, ichthyosis, Gravesophthalmopathy and asthma.

The present invention furthermore relates to a method wherein theimmunoregulatory abnormality is bone marrow or organ transplantrejection or graft-versus-host disease.

The present invention furthermore relates to a method wherein theimmunoregulatory abnormality is selected from the group consisting of:transplantation of organs or tissue, graft-versus-host diseases broughtabout by transplantation, autoimmune syndromes including rheumatoidarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis,multiple sclerosis, systemic sclerosis, myasthenia gravis, type Idiabetes, uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, post-infectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, coeliac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic cirrhosis, hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, cancer, senile dementia, parkison diseases, trauma, andchronic bacterial infection.

In certain embodiments, disorders associated with IRAK are selected fromRheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, SystemicLupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis,Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type Idiabetes, Type II diabetes, Inflammatory Bowel Disease (Cronh's Diseaseand Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic feversyndrome, Cryopyrin-associated periodic syndromes, Schnitzler'ssyndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still'sdisease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis,Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1Receptor Antagonist), Alzheimer's disease, Parkinson's disease, andCancer.

In certain embodiments, the cancer is selected from carcinoma, lymphoma,blastoma (including medulloblastoma and retinoblastoma), sarcoma(including liposarcoma and synovial cell sarcoma), neuroendocrine tumors(including carcinoid tumors, gastrinoma, and islet cell cancer),mesothelioma, schwannoma (including acoustic neuroma), meningioma,adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of thelung and squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer (including metastatic breast cancer), colon cancer, rectalcancer, colorectal cancer, endometrial or uterine carcinoma, salivarygland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer,thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma,testicular cancer, esophageal cancer, tumors of the biliary tract, aswell as head and neck cancer.

In certain embodiments, the cancer is brain, lung, colon, epidermoid,squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal,kidney, liver, ovarian, prostate, colorectal, uterine, rectal,oesophageal, testicular, gynecological, thyroid cancer, melanoma,hematologic malignancies such as acute myelogenous leukemia, multiplemyeloma, chronic myelogneous leukemia, myeloid cell leukemia, glioma,Kaposi's sarcoma, or any other type of solid or liquid tumors. In someembodiments, the cancer is metastatic cancer. In some embodiments, thecancer is colorectal cancer. In some embodiments, the cancer is coloncancer.

In various embodiments, compounds of formula (I), and related formulaeexhibit a IC50 for the binding to IRAK of less than about 5 μM,preferably less than about 1 μM and even more preferably less than about0.100 μM.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to inhibit IRAK activity, usuallybetween about one hour and one week. In-vitro treatment can be carriedout using cultivated cells from a biopsy sample or cell line.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing IRAK-dependent signal transduction pathways in animalsand/or cell culture models or in the clinical diseases mentioned in thisapplication.

Moreover, the subsequent teaching of the present specificationconcerning the use of the compounds according to formula (I) and itsderivatives for the production of a medicament for the prophylactic ortherapeutic treatment and/or monitoring is considered as valid andapplicable without restrictions to the use of the compound for theinhibition of IRAK activity if expedient.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by IRAK activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byIRAK activity. In certain embodiments, the invention provides the use ofa compound according to formula I or physiologically acceptable saltsthereof, for the production of a medicament for the prophylactic ortherapeutic treatment of an IRAK-mediated disorder.

Compounds of formula (I) and/or a physiologically acceptable saltthereof can furthermore be employed as intermediate for the preparationof further medicament active ingredients. The medicament is preferablyprepared in a non-chemical manner, e.g. by combining the activeingredient with at least one solid, fluid and/or semi-fluid carrier orexcipient, and optionally in conjunction with a single or more otheractive substances in an appropriate dosage form.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order toboost the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The methods of the invention can also be used to reducethe likelihood of developing a disorder or even prevent the initiationof disorders associated with IRAK activity in advance or to treat thearising and continuing symptoms.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously incurred disease.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. In certain embodiments, the inventionrelates to a medicament comprising at least one compound according tothe invention and/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with IRAK activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

In various embodiments, the active ingredient may be administered aloneor in combination with other treatments. A synergistic effect may beachieved by using more than one compound in the pharmaceuticalcomposition, i.e. the compound of formula (I) is combined with at leastanother agent as active ingredient, which is either another compound offormula (I) or a compound of different structural scaffold. The activeingredients can be used either simultaneously or sequentially.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor (TNF) antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib dnd/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating agents: such as altretamine, bendamustine, busulfan,carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine,ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol,mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan,mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide,palifosfamide, pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;Platinum Compounds: such as carboplatin, cisplatin, eptaplatin,miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin,satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;DNA altering agents: such as amrubicin, bisantrene, decitabine,mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine,brostallicin, pixantrone, laromustine^(1,3);Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane,sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptiniumacetate, voreloxin;Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin,ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine,vindesine, vinflunine; fosbretabulin, tesetaxel;Antimetabolites: such as asparaginase³, azacitidine, calciumlevofolinate, capecitabine, cladribine, cytarabine, enocitabine,floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine,methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine,thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed,sapacitabine, tegafur^(2,3), trimetrexate;Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin,epirubicin, idarubicin, levamisole, miltefosine, mitomycin C,romidepsin, streptozocin, valrubicin, zinostatin, zorubicin,daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide,buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone,estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant,goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin,nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen,thyrotropin alfa, toremifene, trilostane, triptorelin,diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol,orteronel, enzalutamide^(1,3);Aromatase inhibitors: such as aminoglutethimide, anastrozole,exemestane, fadrozole, letrozole, testolactone; formestane;Small molecule kinase inhibitors: such as crizotinib, dasatinib,erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib,ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib,gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib,dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib,linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib,perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib,tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib,apatinib⁴, cabozantinib S-malate^(1,3), ibrutinib^(1,3), icotinib⁴,buparlisib², cipatinib⁴, cobimetinib^(1,3), idelalisib^(1,3),fedratinib¹, XL-647⁴;Photosensitizers: such as methoxsalen³; porfimer sodium, talaporfin,temoporfin;Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin,cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab,tositumomab, trastuzumab, bevacizumab, pertuzumab^(2,3); catumaxomab,elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab,nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab,rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab,matuzumab, dalotuzumab^(1,2,3) onartuzumab^(1,3), racotumomab¹,tabalumab^(1,3), EMD-525797⁴, nivolumab^(1,3);Cytokines: such as aldesleukin, interferon alfa², interferon alfa2a³,interferon alfa2b^(2,3); celmoleukin, tasonermin, teceleukin,oprelvekin^(1,3), recombinant interferon beta-1a⁴;Drug Conjugates: such as denileukin diftitox, ibritumomab tiuxetan,iobenguane 1123, prednimustine, trastuzumab emtansine, estramustine,gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide,inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox,technetium (99mTc) arcitumomab^(1,3), vintafolide^(1,3);Vaccines: such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴,rindopepimut³, troVax⁴, MGN-1601⁴, MGN-1703⁴; andMiscellaneous: alitretinoin, bexarotene, bortezomib, everolimus,ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine,mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel³,sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin,vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide,entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib,lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin,pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat,thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar,gendicine⁴, picibanil⁴, reolysin⁴, retaspimycin hydrochloride^(1,3),trebananib^(2,3), virulizin⁴, carfilzomib^(1,3), endostatin⁴,immucothel⁴, belinostat³, MGN-1703⁴. (¹Prop. INN (Proposed InternationalNonproprietary Name); ²Rec. INN (Recommended InternationalNonproprietary Names); ³USAN (United States Adopted Name); ⁴no INN).

In another aspect, the invention provides for a kit consisting ofseparate packs of an effective amount of a compound according to theinvention and/or pharmaceutically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally, an effective amount of a further activeingredient. The kit comprises suitable containers, such as boxes,individual bottles, bags or ampoules. The kit may, for example, compriseseparate ampoules, each containing an effective amount of a compoundaccording to the invention and/or pharmaceutically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and an effective amount of a further activeingredient in dissolved or lyophilized form.

Thus, especially preferred is:

(1) A compound of formula I,

-   or a pharmaceutically acceptable salt thereof, wherein:-   A′ is C═O, C(R)₂ or NR;-   L is a divalent group selected from C₃₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   X is CR or N;-   Y is NR or S;-   Z is CR or N;-   R¹ is C₃₋₁₀ aryl, a 3-8 membered saturated or partially unsaturated    carbocyclic ring, a 3-7 membered heterocylic ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; each of    which is optionally substituted;-   R² is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂;-   each R is independently hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; each of which is    optionally substituted; or-   two R groups on the same atom are taken together with the atom to    which they are attached to form a C₃₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted.    (2) A compound as described herein, preferably as described above    and/or below and more preferably as described in Section (1),    wherein A′ is CO, ═CH₂, CHOH, or NH.    (3) A compound as described herein, preferably as described above    and/or below and more preferably as described in Section (1) and/or    Section (2), wherein L is a divalent group selected from phenyl,    cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, furanyl,    furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,    indolenyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl,    1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl,    oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl,    piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,    pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl,    pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,    tetrahydrofuranyl, thiazolyl, thienyl, thiophenyl, oxetanyl, and    azetidinyl, each of which is optionally substituted.    (4) A compound as described herein, preferably as described above    and/or below and more preferably as described in one or more of    Sections (1) to (3), wherein L is a divalent group selected from

(5) A compound as described herein, preferably as described above and/orbelow and more preferably as described in one or more of Sections (1) to(4), wherein R¹ is C₃₋₁₀ aryl.(6) A compound as described herein, preferably as described above and/orbelow and more preferably as described in one or more of Sections (1) to(5), wherein R¹ is

(7) A compound as described herein, preferably as described above and/orbelow and more preferably as described in one or more of Sections (1) to(6), wherein R² is C₁₋₆ aliphatic or 3-7 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.(8) A compound as described herein, preferably as described above and/orbelow and more preferably as described in one or more of Sections (1) to(7), wherein R² is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl,t-butyl, straight chain or branched pentyl, or straight chain orbranched hexyl, or R² is a 4 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.(9) A compound as described herein, preferably as described above and/orbelow and more preferably as described in one or more of Sections (1) to(8), wherein R² is —CF₃,

(10) A compound as described herein, preferably as described aboveand/or below, more preferably as described in one or more of Sections(1) to (10) and especially as described in Section (1), of formula I-a,

or a pharmaceutically acceptable salt thereof.(11) A compound as described herein, preferably as described aboveand/or below, more preferably as described in one or more of Sections(1) to (10) and especially as described in Section (1), of formula I-c,

or a pharmaceutically acceptable salt thereof.(12) A compound as described herein, preferably as described aboveand/or below, more preferably as described in one or more of Sections(1) to (10) and especially as described in Section (1), of formula I-e,

or a pharmaceutically acceptable salt thereof.(13) A compound as described herein, preferably as described aboveand/or below, more preferably as described in one or more of Sections(1) to (10) and especially as described in Section (1), of formula I-h,

or a pharmaceutically acceptable salt thereof.(14) A compound as described herein, preferably as described aboveand/or below, more preferably as described in one or more of Sections(1) to (10) and especially as described in Section (1), selected fromTable 1.(15) A pharmaceutical composition comprising a compound as describedherein, preferably as described above and/or below, more preferably asdescribed in one or more of Sections (1) to (14) and especially asdescribed in Section (1), and a pharmaceutically acceptable adjuvant,carrier, or vehicle.(16) A method for inhibiting IRAK, or a mutant thereof, activity in apatient or in a biological sample, comprising the step of administeringto said patient or contacting said biological sample with a compound asdescribed herein, preferably as described above and/or below, morepreferably as described in one or more of Sections (1) to (14) andespecially as described in Section (1), or a physiologically acceptablesalt thereof.(17) A method for treating an IRAK-mediated disorder in a patient inneed thereof, comprising the step of administering to said patient acompound as described herein, preferably as described above and/orbelow, more preferably as described in one or more of Sections (1) to(14) and especially as described in Section (1).(18) A method as described herein, preferably as described above and/orbelow, more preferably as described in Section (16) and/or Section (17)and especially as described in Section (17), wherein the disorder isselected from Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis,Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis,Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type Idiabetes, Type II diabetes, Inflammatory Bowel Disease (Cronh's Diseaseand Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic feversyndrome, Cryopyrin-associated periodic syndromes, Schnitzler'ssyndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still'sdisease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease,andometriosis; Sepsis, Stroke, Atherosclerosis, Celiac disease, DIRA(Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease,Parkinson's disease, and Cancer.(19) A method for treating a subject as described herein, preferably asdescribed above and/or below and more preferably a method for treatingcancer in a subject, said method comprising the step of administering tosaid subject a compound as described herein, preferably as describedabove and/or below, more preferably as described in one or more ofSections (1) to (14) and especially as described in Section (1), or aphysiologically acceptable salt thereof.(20) A method as described herein, preferably as described above and/orbelow, more preferably as described in Section (16), Section (17),Section (18) and/or Section (19) and especially as described in Section(18), wherein the disorder is selected from Rheumatoid Arthritis,Systemic Lupus Erythematosus, Lupus nephritis, and Multiple Sclerosis.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment is administered afterone or more symptoms have developed. In other embodiments, treatment isadministered in the absence of symptoms. For example, treatment isadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment is also continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

The compounds and compositions, according to the method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided above. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention are administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 100mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

In certain embodiments, a therapeutically effective amount of a compoundof the formula (I), and related formulae and of the other activeingredient depends on a number of factors, including, for example, theage and weight of the animal, the precise disease condition whichrequires treatment, and its severity, the nature of the formulation andthe method of administration, and is ultimately determined by thetreating doctor or vet. However, an effective amount of a compound isgenerally in the range from 0.1 to 100 mg/kg of body weight of therecipient (mammal) per day and particularly typically in the range from1 to 10 mg/kg of body weight per day. Thus, the actual amount per dayfor an adult mammal weighing 70 kg is usually between 70 and 700 mg,where this amount can be administered as an individual dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound per se.

In certain embodiments, the pharmaceutical formulations can beadministered in the form of dosage units, which comprise a predeterminedamount of active ingredient per dosage unit. Such a unit can comprise,for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularlypreferably 5 mg to 100 mg, of a compound according to the invention,depending on the disease condition treated, the method of administrationand the age, weight and condition of the patient, or pharmaceuticalformulations can be administered in the form of dosage units whichcomprise a predetermined amount of active ingredient per dosage unit.Preferred dosage unit formulations are those which comprise a daily doseor part-dose, as indicated above, or a corresponding fraction thereof ofan active ingredient. Furthermore, pharmaceutical formulations of thistype can be prepared using a process, which is generally known in thepharmaceutical art.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms optionally contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions are formulated according to the known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation are also a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This is accomplished by the useof a liquid suspension of crystalline or amorphous material with poorwater solubility. The rate of absorption of the compound then dependsupon its rate of dissolution that, in turn, may depend upon crystal sizeand crystalline form. Alternatively, delayed absorption of aparenterally administered compound form is accomplished by dissolving orsuspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form also optionally comprises buffering agents.

Solid compositions of a similar type are also employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype are also employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms optionally also comprisebuffering agents. They optionally contain opacifying agents and can alsobe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as required. Ophthalmicformulation, ear drops, and eye drops are also contemplated as beingwithin the scope of this invention. Additionally, the present inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms can be made by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting IRAK activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting IRAK, or a mutant thereof, activity in a biological sample ina positive manner, comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

The compounds of the invention are useful in-vitro as unique tools forunderstanding the biological role of IRAK, including the evaluation ofthe many factors thought to influence, and be influenced by, theproduction of IRAK and the interaction of IRAK. The present compoundsare also useful in the development of other compounds that interact withIRAK since the present compounds provide important structure-activityrelationship (SAR) information that facilitate that development.Compounds of the present invention that bind to IRAK can be used asreagents for detecting IRAK in living cells, fixed cells, in biologicalfluids, in tissue homogenates, in purified, natural biologicalmaterials, etc. For example, by labeling such compounds, one canidentify cells expressing IRAK. In addition, based on their ability tobind IRAK, compounds of the present invention can be used in in-situstaining, FACS (fluorescence-activated cell sorting), sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), ELISA(enzyme-linked immunoadsorptive assay), etc., enzyme purification, or inpurifying cells expressing IRAK inside permeabilized cells. Thecompounds of the invention can also be utilized as commercial researchreagents for various medical research and diagnostic uses. Such uses caninclude but are not limited to: use as a calibration standard forquantifying the activities of candidate IRAK inhibitors in a variety offunctional assays; use as blocking reagents in random compoundscreening, i.e. in looking for new families of IRAK ligands, thecompounds can be used to block recovery of the presently claimed IRAKcompounds; use in the co-crystallization with IRAK enzyme, i.e. thecompounds of the present invention will allow formation of crystals ofthe compound bound to IRAK, enabling the determination ofenzyme/compound structure by x-ray crystallography; other research anddiagnostic applications, wherein IRAK is preferably activated or suchactivation is conveniently calibrated against a known quantity of anIRAK inhibitor, etc.; use in assays as probes for determining theexpression of IRAK in cells; and developing assays for detectingcompounds which bind to the same site as the IRAK binding ligands.

The compounds of the invention can be applied either themselves and/orin combination with physical measurements for diagnostics of treatmenteffectiveness. Pharmaceutical compositions containing said compounds andthe use of said compounds to treat IRAK-mediated conditions is apromising, novel approach for a broad spectrum of therapies causing adirect and immediate improvement in the state of health, whether inhuman or in animal. The orally bioavailable and active new chemicalentities of the invention improve convenience for patients andcompliance for physicians.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Modulation of IRAK, or a mutant thereof, activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ transplantation, biological specimen storage,and biological assays.

The term “about” as used herein with respect to numbers, figures, rangesand/or amounts is preferably meant to mean “circa” and/or“approximately”. The meaning of those terms is well known in the art andpreferably includes a variance, deviation and/or variability of therespective number, figure, range and/or amount of plus/minus 15% andespecially of plus/minus 10%.

In any case, the term “about” as used herein with respect to numbers,figures, ranges and/or amounts is preferably meant to mean “circa”and/or “approximately”. The meaning of those terms is well known in theart and preferably includes a variance, deviation and/or variability ofthe respective number, figure, range and/or amount of at leastplus/minus 5% or of plus/minus 5%.

The terms “disorder(s)” and “disease(s)” as used herein are well-knownand understood in the art. In the context of the present invention theyare preferably used as synonyms and thus are preferably interchangeable,if the context they are used herein does not strongly implicateotherwise.

In the medical context, including, but not limited to treatmentregimens, dosing schedules and clinical trial designs, for convenienceand/or ease of use by patients, medical staff and/or physicians, as wellas reliability and/or reproducibility of results etc., the terms“week”/“a week”, “month”/“a month” and/or “year”/“a year” can used withslight deviations from the definitions of the Gregorian calendar. Forexample, in said medical context, a month is often referred to as 28days, and a year is often referred to 48 weeks.

Thus, in the context of the instant invention, the term “week” or “aweek” preferably refers to a period of time of about 5, about 6 or about7 days, more preferably about 7 days.

In the medical context, the term “month” or “a month” preferably refersto a period of time of about 28, about 29, about 30 or about 31 days,more preferably about 28, about 30 or about 31 days.

In the medical context, the term “year” or “a year” preferably refers toa period of time of about 12 months or to a period of time of about 48,about 50, or about 52 weeks, more preferably 12 months, or about 48 orabout 52 weeks.

Especially preferred according to the invention is subject matter asdescribed herein, wherein the characteristics of two or more preferred,more preferred and/or especially preferred embodiments, aspects and/orsubjects are combined into one embodiment, aspect and/or subject.Preferably, according to this invention, preferred subjects orembodiments can be combined with other preferred subjects orembodiments; more preferred subjects or embodiments can be combined withother less preferred or even more preferred subjects or embodiments;especially preferred subjects or embodiments can be combined with otherjust preferred or just even more preferred subjects or embodiments, andthe like.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

The symbols and conventions used in the following descriptions ofprocesses, schemes, and examples are consistent with those used in thecontemporary scientific literature, for example, the Journal of theAmerican Chemical Society or the Journal of Biological Chemistry.

All NMR experiments were recorded on Bruker Avance III 400 NMRSpectrometer equipped with a Bruker PABBO BB-1H/D Z GRD probe at 400 MHzfor proton NMR or a Bruker DPX-300 MHz. Most deuterated solventscontained typically 0.03% to 0.05% v/v tetramethylsilane, which was usedas the reference signal (set at δ 0.00 for both ¹H and ¹³C). In caseswhere the deuterated solvents did not contain tetramethylsilane, theresidual non-deuterated solvent peaks were used as a reference signal,as per published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997).Chemical shifts are expressed in parts per million (ppm, 6 units).Coupling constants are in units of hertz (Hz). Splitting patternsdescribe apparent multiplicities and are designated as s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), qt (quintuplet) orbrs (broad singlet).

The following abbreviations refer to the abbreviations used below:

Ac (acetyl); ACN (acetonitrile); atm (atmosphere); DIEA (Di-isopropylethylamine); ° C. (degrees centigrade); DMF (dimethylformamide); DMSO(dimethylsulfoxide); dppf (1,1′-bis-diphenyl phosphine ferrocene); eq(equivalent); EtOAc (Ethylacetate); g (gram); HATU(N-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminiumhexafluorophosphate); HPLC (High Performance Liquid Chromatography); h (hour); LC(liquid Chromatography); LDA (lithium diisopropylamine); MeOH(methanol); min (minute); mL (milliliter); mmol (millimole); MS (Massspectroscopy); NMR (Nuclear Magnetic Resonance); 0/N (overnight); PE(Petroleum Ether); RT (room temperature); TBDMS(tert-Butyldimethylsilyl); TEA (triethylamine); TFA (trifluoroaceticacid); THF (tetrahydofurane); TMS (trimethylsilyl).

UPLC/MS analyses were performed on a Waters AquityH with SQ detector(ESI) and LC/MS on an Agilent 1200 Series with a quadupole detector or aSHIMADZU LC-MS machine consisting of an UFLC 20-AD system and a LCMS2020 MS detector.

Purity was measured using a Waters aquityH equipped with a XBridgecolumn C8, 3.5 μm, 4.6×50 mm, using water/ACN with 0.1% TFA as eluent,gradient from 0 to 100% in 8 min (reported as ‘UPLC’), unless otherwiseindicated.

The microwave reactions were conducted using Biotage Initiator MicrowaveSynthesizer using standard protocols that are known in the art.

The compounds of the invention were prepared from readily availablestarting materials by several synthetic approaches, using bothsolution-phase and solid-phase chemistry protocols or mixed solution andsolid phase protocols. Examples of synthetic pathways are describedbelow in the examples. Unless otherwise stated, compounds of theinvention obtained as a racemic mixture can be separated to provide anenantiomerically enriched mixture or a pure enantiomer.

The commercially available starting materials used in the followingexperimental description were purchased from Sigma-Aldrich or Fisherunless otherwise reported.

Intermediate 1:3-(4-aminophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (300 mg,1.37 mmol, 1.0 eq), 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(310 mg, 1.36 mmol, 1.0 eq), Pd(dppf)Cl₂ (100 mg, 0.14 mmol, 0.10 eq) inDioxane (12 mL) and a solution of sodium bicarbonate (110 mg, 1.31 mmol,1.0 eq) in water (4 mL) was purged with nitrogen in a sealed tube beforebeing heated at 100° C. for 2 h. The resulting solution was thenconcentrated under reduced pressure, diluted with water (50 mL) andextracted ethyl acetate (3×20 mL). Combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated to give thetitle compound (300 mg, 82%) as a yellow solid. LC/MS: 241.0 [M+H].

Intermediate 2:3-(4-Amino-2-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

A mixture of 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (231mg; 1.01 mol, 1.2 eq),3-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(200 mg; 0.84 mmol, 1 eq), Pd(dppf)Cl₂.DCM (138 mg; 0.17 mmol; 0.2 eq)and cesium carbonate (605 mg; 1.8 mmol; 2.2 eq) in 1,4-dioxane (4 mL)and water (1 mL) was stirred overnight at 100° C. under nitrogenatmosphere. The reaction mixture was then filtered through a celite pad.The filtrate was diluted with EtOAc (50 mL) and washed with 1M NaOH(2×30 mL) and brine (2×30 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated. Purification by flash chromatographyon silica (DCM:MeOH, gradient 99:1 to 80:20) afforded the title compound(95 mg, 44%) as a brown solid. LC/MS: 259.1 [M+H].

Intermediate 3:3-(4-Amino-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(200 mg; 0.84 mmol) as a white solid (90 mg, 41%).

Intermediate 4:3-(4-Amino-3-chloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from4-amino-3-chlorophenylboronic acid pinacol ester (200 mg; 0.79 mmol) asa white solid (111 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H),8.88 (s, 1H), 8.33 (t, J=8.4 Hz, 1H), 8.26 (s, 1H), 7.48-7.34 (m, 6H),6.42 (s, 1H), 5.76 (s, 1H), 3.95 (s, 3H), 2.40 (s, 3H), 1.29 (s, 9H).UPLC: (254 nm) 100% purity; Rt 1.66 min. UPLC/MS: 275.2 [M+H].

Intermediate 5:5-(4-Amino-2-fluoro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from5-Bromo-thieno[2,3-d]pyrimidin-4-ylamine (233 mg; 1.0 mmol) and4-amino-2-fluorophenylboronic acid pinacol ester (200 mg; 0.84 mmol) asa yellow oil (126 mg, 57%).

Intermediate 6:5-(4-Amino-3-fluoro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from4-amino-3-fluorophenylboronic acid pinacol ester (200 mg; 0.84 mmol) and5-Bromo-thieno[2,3-d]pyrimidin-4-ylamine (233 mg; 1.0 mmol) as a whitesolid (132 mg, 60%).

Intermediate 7:3-(4-Amino-2-chloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (216 mg; 1.0mmol) and3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg;0.79 mmol) as a white solid (169 mg, 78%).

Intermediate 8:3-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

A solution of 4-nitrophenyl chloroformate (440 mg, 2.07 mmol, 1.0 eq),dichloromethane (5 mL), pyridine (235 mg, 2.91 mmol, 1.4 eq) and3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (prepared asdescribed in Molecules, 2014, Volume 19, Issue 2, 2004-2028, 520 mg,1.92 mmol, 0.93 eq) in DCM (5 mL) maintained under nitrogen atmospherewas stirred at 5° C. for 2 h before the addition of2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (470 mg, 1.88mmol, 0.9 eq) and DIEA (520 mg, 3.94 mmol, 1.9 eq). The resultingreaction mixture was stirred for an additional 3 h at RT. The solventwas removed under reduced pressure and the crude was purified by flashchromatography on silica (EtOAc:PE; 1:1) to afford the title compound asa yellow solid (300 mg, 19%).

Intermediate 9:5-(4-Amino-2-chloro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from5-Bromo-thieno[2,3-d]pyrimidin-4-ylamine (218 mg; 0.95 mmol; 1.2 eq) and3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg;0.79 mmol; 1.0 eq) as a white amorphous solid (71 mg, 32%).

Intermediate 10:5-(4-Amino-2-chloro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from5-Bromo-thieno[2,3-d]pyrimidin-4-ylamine (218 mg; 0.95 mmol; 1.20 eq.)and 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200mg; 0.79 mmol; 1.0 eq) as a yellow oil (71 mg, 32%).

Intermediate 11:1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea

A solution of (4-isocyanatophenyl)boronic acid, pinacol ester (200 mg;0.82 mmol; 1.0 eq) in DCM (1 mL) was added slowly to a solution of5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (187 mg; 0.82 mmol; 1.0 eq)in DCM (17 mL) maintained under nitrogen atmosphere and at 0° C. Thereaction mixture was then allowed to warm at RT and stirred for 16 h.The solvent was removed under reduced pressure and the crude waspurified by Preparative HPLC (column C18 X-Bridge 30×250 mm, 10 um,gradient 30-95% ACN with 0.1% ammonium hydroxide) to give the titlecompound as a white solid (172 mg, 45%).

Intermediate 12: 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine Step1:N-[(2,4-dimethoxyphenyl)methyl]-3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine

A solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.10 g, 3.74mmol, 1.00 eq) and (2,4-dimethoxyphenyl)methanamine (1.97 g, 11.2 mmol,3.0 eq) in DMSO (20 mL) was stirred 0/N at 120° C. under nitrogenatmosphere. The reaction mixture was then diluted with water (30 mL) andextracted with DCM (2×30 mL). Combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated.Purification by flash chromatography on silica (DCM:MeOH, gradient 100:1to 10:1) afforded the title compound as a brown solid (1.3 g, 67%).LC/MS: 410.9 [M+H].

Step 2: 3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine

A solution ofN-[(2,4-dimethoxyphenyl)methyl]-3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine(1.3 g, 2.54 mmol, 1.0 eq) in TFA (10 mL) was heated for 3 h at 50° C.TFA was then removed under reduced pressure and the resulting oil wasdiluted with EtOAc (50 mL). It was washed with sodium bicarbonate (30mL), dried over anhydrous sodium sulfate, filtered and concentrated togive the title compound as a brown solid (450 mg, 58%). LC/MS: 260.8[M+H].

Step 3: 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine

A mixture of 3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine (100 mg, 0.33mmol, 1.0 eq), sodium hydride (19 mg, 0.79 mmol, 1.20 equiv) and MeI (56mg, 0.39 mmol, 1.2 eq) was stirred for 2 h at RT in DMF (3 mL). Thereaction was then quenched by the addition of 5 mL of sat. NH₄Cl andextracted with DCM (2×10 mL). Combined organic layers were washed withbrine (2×10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by flash chromatography on silica (EtOAc:PE,gradient from 1:10 to 1:1) afforded the title compound as a brown solid(60 mg, 62%). LC/MS (Column Kinetex EVO C18 100 A, 3.0×50 mm, 2.6 um;water/5 mM NH₄HCO₃/Acetonitrile from 10 to 95%, 254 nm): 93% purity;274.7 [M+H].

Intermediate 13:3-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

The title compound was obtained following a similar procedure asdescribed for intermediate 8 but starting from3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (520 mg, 1.92mmol, 1.00 eq) and 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (440mg, 1.91 mmol, 0.99 eq) as a yellow solid (600 mg, 59%). LC/MS (ColumnShim-pack XR-ODS, 3.0×50 mm, 2.2 um; Water/ACN with 0.05% TFA, gradientfrom 5 to 100% in 2.2 min, hold 1.0 min; 254 nm): 86.0% purity; 503.2[M+H].

Intermediate 14:N-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide

A solution of HATU (228 mg, 0.57 mmol, 1.05 eq) in DMF (2 mL) was addeddropwise to a solution of2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid (150 mg,0.54 mmol, 1.0 eq),3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (180 mg, 0.63mmol, 1.16 eq) and DIEA (222 mg, 1.63 mmol, 3.0 eq) in DMF (3 mL). Thereaction mixture was then stirred at 15° C. for 16 h and concentratedunder reduced pressure. Purification by preparative TLC on silica(PE:EtOAc, 5:1) afforded the title compound as a yellow oil (65 mg,16%). LC/MS: 502.4 [M+H].

Intermediate 15:N-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-2-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamideStep 1:2-(4-bromo-2-fluorophenyl)-N-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}acetamide

The title compound was obtained following a similar procedure asdescribed for intermediate 14 but starting from 4-bromo-2-fluorobenzoicacid (500 mg, 2.17 mmol, 1.0 eq) and3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (611 mg, 2.26mmol, 1.0 eq) as a yellow solid (1.38 g, 100%). LC/MS (Column KinetexEVO C18 100 A, 3.0×50 mm, 2.6 um; water/5 mM NH₄HCO₃/Acetonitrile from10 to 95%, 254 nm): 76.0% purity; 472.2 [M+H].

Step 2:N-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-2-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide

A mixture of2-(4-bromo-2-fluorophenyl)-N-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl]acetamide(200 mg, 0.32 mmol, 1.0 eq),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(133 mg, 0.50 mmol, 1.55 eq), Pd(dppf)Cl₂.CH₂Cl₂ (33 mg, 0.04 mmol, 0.12eq) and AcOK (66 mg, 0.64 mmol, 2.0 eq) in dioxane (5 mL) in a sealedtube was purged with nitrogen before being heated at 100° C. for 3.5 h.Solvent was then removed under reduced pressure and the residue wasdiluted with DCM, washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated to give the title compound as a blackoil (300 mg, 100%). LC/MS): 520.3 [M+H].

Intermediate 16:2-[5-({[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl}amino)-1-(4-methylphenyl)-1H-pyrazol-3-yl]-2-methylpropylacetate

The title compound was obtained following a similar procedure asdescribed for intermediate 8 but starting from2-[5-amino-1-(4-methylphenyl)-1H-pyrazol-3-yl]-2-methylpropyl acetate(prepared as described in Journal of Medicinal Chemistry, 46(22),4676-4686; 2003; 290 mg, 0.96 mmol, 0.93 eq) and2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 0.94mmol, 0.90 eq) as yellow solid (300 mg, 51%). LC/MS: 567.2 [M+H].

Intermediate 17:3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-amine Step 1:3-(3-methyloxetan-3-yl)-3-oxopropanenitrile

A solution of t-BuOK (9 g, 78.60 mmol, 2.00 eq) in THF (30 mL) was addeddropwise to a solution of benzyl 3-methyloxetane-3-carboxylate (9 g,39.28 mmol, 1.0 eq) and MeCN (2.1 mL, 39.95 mmol, 1.02 equiv) in THF(100 mL) maintained under nitrogen atmosphere. The reaction mixture wasstirred for 16 h at 25° C. It was then concentrated under reducedpressure and purified by flash chromatography on silica (EtOAc:PE,gradient from 1:4 to 1:2) to give the title compound as a yellow oil(4.0 g, 66%).

Step 2: 3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-amine

A solution of 3-(3-methyloxetan-3-yl)-3-oxopropanenitrile (7.8 g, 50.4mmol, 1.0 eq), (4-methylphenyl)hydrazine hydrochloride (8.17 g, 50.5mmol, 1.0 eq) and AcOH (310 mg, 5.06 mmol, 0.1 eq) in EtOH (150 mL) wasstirred for 16 h at 50° C. The solvent was removed under reducedpressure and purification by flash chromatography on silica (EtOAc:PE,gradient from 1:4 to 1:2) then on a C18-silica gel column (MeOH:water,gradient from 1:4 to 1:3) to give the title compound as a yellow solid(1 g, 9%). 1H NMR (300 MHz, DMSO-d6) δ 7.45 (d, J=8.4 Hz, 2H), 7.26 (d,J=8.1 Hz, 2H), 5.46 (s, 1H), 5.27 (s, 2H), 4.78 (d, J=5.2 Hz, 2H), 4.40(d, J=5.2 Hz, 2H), 2.34 (s, 3H), 1.5 9 (s, 3H). LC/MS (Column KinetexEVO C18 100 A, 3.0×50 mm, 2.6 um; water/5 mM NH₄HCO₃/Acetonitrile from10 to 95%, 254 nm): 97% purity; 244.2 [M+H]; mp: 136-140° C.

Intermediate 18:1-[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea

The title compound was obtained following a similar procedure asdescribed for intermediate 8 but starting from3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-amine (101 mg,0.40 mmol, 1.0 eq) and2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (114 mg, 0.40mmol, 1.01 eq) as a yellow solid (140 mg, 54%). LC/MS (Column PhenomenexKinetext 3.0×50 mm, 2.7 um; Water/ACN with 0.05% TFA; gradient from 5%to 100% in 1.1 min, hold 0.5 min; 254 nm): 80% purity; 523.3 [M+H].

Intermediate 19:N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-hydroxy-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamideStep 1:N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-[(trimethylsilyl)oxy]acetamide

Chlorotrimethylsilane (188 mg, 1.64 mmol, 2.0 eq) was added to asolution of 2-(4-bromophenyl)-2-hydroxyacetic acid (200 mg, 0.82 mmol,1.00 eq), 4-dimethylaminopyridine (10.6 mg, 0.08 mmol, 0.10 eq) andpyridine (137 mg, 1.65 mmol, 2.00 eq) in DCM (2 mL) maintained undernitrogen atmosphere. The reaction mixture was stirred at RT for 4 h. Itwas then cooled down to 0° C. DMF (0.2 mL) followed by Oxalyl chloride(115 mg, 0.86 mmol, 1.05 eq) were added dropwise and the reactionmixture was stirred for 1 h at 0° C. It was allowed to warm to RT beforethe addition of a solution of3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (218 mg, 0.86 mmol,1.04 eq) in pyridine (0.2 mL) and stirred for an additional 2 h at 15°C. After dilution with water, the mixture was extracted with DCM (3×5mL). Combined organic layers were washed with sat. NaHCO₃ and brine,dried over anhydrous sodium sulfate, filtered and concentrated.Purification on preparative TLC (PE:EtOAc, 5:1) afforded the titlecompound a as yellow solid (95 mg, 24%).

Step 2:N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-hydroxy-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide

The title compound was obtained following a similar procedure asdescribed for intermediate 15, step 2, but starting from2-(4-bromophenyl)-N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-hydroxyacetamide(85 mg, 0.17 mmol, 1.0 eq) as a yellow solid (80 mg, 58%). LC/MS: 490.4[M+H].

Intermediate 20:2-(5-Amino-1-p-tolyl-1H-pyrazol-3-yl)-2-methyl-propionitrile

The title compound was obtained following a similar procedure asdescribed for intermediate 17, step 2, but starting from2,2-Dimethyl-3-oxopentanedinitrile. LC/MS: 241.1 [M+H].

Intermediate 21:2-Chloro-3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 15, step 2, but starting from4-Bromo-2-chloro-3-fluoro-phenylamine (100 mg; 0.45 mmol) as a brownsolid (100 mg, 83%). UPLC/MS: 272.3 [M+H].

Intermediate 22:5-(4-Amino-3-chloro-2-fluoro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from5-Bromo-thieno[2,3-d]pyrimidin-4-ylamine (102 mg; 0.44 mmol; 1.2 eq) and2-Chloro-3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(100 mg; 0.37 mmol; 1 eq) as a yellow solid (31 mg, 29%).

Intermediate 23:1-(4-methylphenyl)-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine

A solution of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (4 g, 19mmol, 1.0 eq) and (4-methylphenyl)hydrazine hydrochloride (3.3 g, 19.8mmol, 1.04 eq) in EtOH (50 mL) was heated at 80° C. for 16 h. Thesolvent was removed under reduced pressure and the residue was purifiedby flash chromatography on C18-silica (water:MeOH; 1:1) to give thetitle compound as a yellow solid (2 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ7.43 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 5.50 (s, 1H), 5.29 (s,2H), 2.34 (s, 3H), 1.4 (s, 6H). LC/MS: 284.1 [M+H]. mp: 90° C.

Intermediate 24:5-(4-aminocyclohex-1-en-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineStep 1: tert-butylN-(4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohex-3-en-1-yl)carbamate

The title compound was obtained following a similar procedure asdescribed for intermediate 2 but starting from tert-butylN-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]carbamate(501 mg, 1.47 mmol, 1.20 eq) and5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (372 mg, 1.22 mmol,1.00 eq) as a brown solid (200 mg, 43%). LC/MS (Column Ascentis ExpressC18, 3.0*×50 mm, 0.7 um; Water/ACN with 0.05% TFA gradient from 5 to100% in 1.2 min, hold 0.5 min; 254 nm): 90% purity; 344.0 [M+H].

Step 2:5-(4-aminocyclohex-1-en-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution of tert-butylN-(4-[4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl]cyclohex-3-en-1-yl)carbamate(200 mg, 0.52 mmol, 1.0 equiv, 90%) and trifluoroacetic acid (1 mL) inDCM (5 mL) was stirred for 3 h at 25° C. The pH was then adjusted to 8by addition of NH₄OH and the mixture was diluted with DCM (20 mL).Organic phase was washed with brine (2×20 mL), dried over anhydroussodium sulfate, filtered and concentrated to give the title compound asa brown solid (130 mg, 92%). LC/MS (Column Ascentis Express C18, 3.0×50mm, 2.7 um; Water/ACN with 0.05% TFA, Gradient from 5% to 100% in 1.2min, hold 0.5 min; 254 nm): 90% purity; 244.0 [M+H].

Intermediate 25:3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

A solution of 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (300mg, 1.18 mmol, 1.0 eq) and DIEA (641 mg, 4.7 mmol, 4.0 eq) in DCM (1 mL)was added dropwise to a solution of triphosgene (69 mg, 0.22 mmol, 0.6eq) in DCM (5 mL) maintained at 0° C. and under nitrogen atmosphere. Thereaction mixture was stirred for 20 min at 0° C. and added to a solutionof 2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (323 mg, 1.3mmol, 1.1 eq) in DCM (3 mL). The resulting reaction mixture was stirredfor 3 h at RT, washed with a saturated solution of NH₄Cl (2×10 mL) andbrine (1×10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by flash chromatography on silica (DCM:MeOH;3:1) afforded the title compound as a brown solid (180 mg, 20%). LC/MS:493.0 [M+H].

Example 1:1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-3-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}urea(15)

A solution of 3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine(prepared as described in Molecules, 2014, Volume 19, Issue 2,2004-2028, 257 mg, 1.00 mmol, 1.0 eq) in DCM (2 mL) was added dropwiseto a solution of 4-nitrophenyl chloroformate (220 mg, 1.09 mmol, 1.1 eq)and pyridine (120 mg, 1.52 mmol, 1.6 eq) in DCM (20 mL) maintained at 5°C. 3-(4-aminophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(intermediate 1, 240 mg, 1.00 mmol, 1.0 eq) and DIEA (260 mg, 2.01 mmol,2.0 eq) were then added and the resulting reaction mixture was stirredat 25° C. for 16 h. It was then concentrated under vacuum and purifiedby Prep-HPLC (Column, Gemini-NX C18 AXAI, 21.2×150 mm, Sum; Water with10 mM NH₄HCO₃ and ACN gradient from 40% to 63% in 10 min) to afford thetitle compound as a yellow solid (6 mg, 19%). 1H NMR (400 MHz, DMSO-d6):9.24 (s, 1), 8.48 (s, 1), 8.25 (s, 1), 7.59 (m, 4), 7.43 (m, 4), 6.40(s, 1), 3.94 (s, 3), 2.98 (t, 1, J=6.8 Hz), 1.28 (s, 9), 1.25 (d, 6,J=7.2 Hz); LC/MS (Column Shim-pack XR-ODS, 3.0×50 mm, 2.2 um; Water/CANwith 0.05% TFA, Gradient from 5 to 100% in 3.6 min, hold 1.0 min; 254nm): (purity) 97.9%; 524.3 [M+H].

Example 2:1-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(2)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (67 mg; 0.29 mmol; 1.5 eq)and3-(4-Amino-2-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine(intermediate 2, 50 mg; 0.19 mmol; 1.0 eq) as a white solid (15 mg,15%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.88 (s, 1H), 8.33 (t,J=8.4 Hz, 1H), 8.26 (s, 1H), 7.48-7.34 (m, 6H), 6.42 (s, 1H), 5.76 (s,1H), 3.95 (s, 3H), 2.40 (s, 3H), 1.29 (s, 9H). UPLC: (254 nm) 100%purity; Rt 3.5 min. UPLC/MS: 514.5 [M+H].

Example 3:1-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-phenyl]-3-[5-tert-butyl-2-(4-isopropyl-phenyl)-2H-pyrazol-3-yl]-urea(11)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (86 mg, 0.32mmol, 1.0 eq) as a white solid (20 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ9.42 (s, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 7.66-7.60 (m, 1H), 7.46-7.39(m, 5H), 7.25-7.21 (m, 1H), 6.39 (s, 1H), 3.94 (s, 3H), 3.00-2.95 (m,1H), 1.28 (s, 9H), 1.26-1.24 (d, J=6.9 Hz, 6H); LC/MS (Column KinetexEVO C18 100 A, 3.0×50 mm, 2.6 um, water with 5 mM NH₄HCO₃/ACN, Gradientfrom 10% to 95% in 2.0 min, hold 0.5 min; 254 nm): 99.6% purity; 542.3[M+H]. mp: 160.0 to 162.0° C.

Example 4:1-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(6)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (44 mg; 0.19 mmol; 1.0 eq)and3-(4-Amino-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine(intermediate 3, 50 mg; 0.19 mmol; 1.0 eq) as a white solid (15 mg,15%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.88 (s, 1H), 8.33 (t,J=8.6 Hz, 1H), 8.26 (s, 1H), 7.50-7.31 (m, 6H), 6.42 (s, 1H), 3.95 (s,3H), 2.40 (s, 3H), 1.29 (s, 8H). UPLC: (254 nm) 100% purity; Rt 3.5 min.UPLC/MS: 514.5 [M+H].

Example 5:1-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(4)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (658 mg; 2.87 mmol; 1.0 eq)and3-(4-Amino-3-chloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine(intermediate 4, 789 mg; 2.87 mmol; 1.0 eq) as white solid (41 mg, 3%).1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.77 (s, 1H), 8.30 (d, J=8.6Hz, 1H), 8.26 (s, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.58 (dd, J=8.6, 2.1 Hz,1H), 7.45-7.33 (m, 4H), 6.41 (s, 1H), 3.95 (s, 3H), 2.39 (s, 3H), 1.29(s, 9H). UPLC: (254 nm) 100% purity; Rt 3.65 min. UPLC/MS: 530.5 [M+H].

Example 6:1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-3-fluoro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(12)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (73 mg; 0.32 mmol) and3-(4-Amino-2-fluoro-phenyl)-isothiazolo[5,4-d]pyrimidin-4-ylamine(intermediate 5, 83 mg; 0.32 mmol) as a white solid (34 mg, 20%). 1H NMR(400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.61 (dd,J=12.4, 2.1 Hz, 1H), 7.52 (s, 1H), 7.45-7.33 (m, 5H), 7.23 (dd, J=8.4,2.1 Hz, 1H), 6.39 (s, 1H), 2.39 (s, 3H), 1.29 (s, 8H). UPLC: (254 nm)100% purity; Rt 3.81 min. UPLC/MS: 516 [M+H].

Example 7:1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-2-fluoro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(9)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (116 mg; 0.51 mmol) and5-(4-Amino-3-fluoro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine(intermediate 6, 132 mg; 0.51 mmol) as a yellow solid (27 mg, 10%). 1HNMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.88 (s, 1H), 8.35 (s, 1H), 8.29(t, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.44-7.34 (m, 5H), 7.29-7.19 (m, 1H),6.41 (s, 1H), 2.40 (s, 3H), 1.29 (s, 10H). UPLC: (254 nm) 100% purity;Rt 3.7 min. UPLC/MS: 516 [M+H].

Example 8:1-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(8)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (42 mg; 0.18 mmol) and3-(4-Amino-2-chloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine(intermediate 7, 50 mg, 0.18 mmol) as white solid (8 mg, 8%). 1H NMR(400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 7.86 (d,J=1.9 Hz, 1H), 7.49-7.24 (m, 5H), 6.39 (s, 1H), 3.94 (s, 3H), 2.39 (s,3H), 1.30 (s, 9H). UPLC: (254 nm) 96% purity; Rt 3.63 min. UPLC/MS:530.3 [M+H].

Example 9:1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-3-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}urea(10)

A mixture of3-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl]-1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea(intermediate 8, 160 mg, 0.29 mmol, 1.0 eq),3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (101 mg, 0.35 mmol,1.2 eq), Pd(dppf)Cl₂.CH₂Cl₂ (25 mg, 0.03 mmol, 0.10 eq) and KOAc (90.4mg, 0.90 mmol, 3.1 eq) in dioxane (15 mL) and water (1.5 mL) was purgedwith nitrogen and heated in MW for 1 h at 80° C. in a sealed tube.Solvent was removed under reduced pressure and the residue was purifiedby flash chromatography on silica (DCM:MeOH, 20:1) to afford the titlecompound as a white solid (30 mg, 19%). mp: 166-168° C. 1H NMR (400 MHz,DMSO-d6) δ 9.13-9.12 (m, 1H), 8.94 (s, 1H), 8.34-8.30 (m, 1H), 8.24 (s,1H), 7.45-7.41 (m, 6H), 6.40 (s, 1H), 3.92 (s, 3H), 2.99-2.95 (m, 1H),1.26-1.23 (m, 15H). LC/MS (Column XBridge C18, 4.6×50 mm, 3.5 um; Waterwith 5 mM NH₄HCO₃/ACN; Gradient from 10% to 95% in 1.2 min, hold 1.0min; 254 nm): 99% (purity); 542.2 [M+H].

Example 10:1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-3-chloro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(14)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (58 mg; 0.26 mmol; 1.0 eq)and 5-(4-Amino-2-chloro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine(intermediate 9, 71 mg; 0.26 mmol; 1.0 eq) as a yellow foam (12 mg,12%). 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.50 (s, 1H), 8.34 (s,1H), 7.87 (d, J=2.0 Hz, 1H), 7.48 (s, 1H), 7.44-7.32 (m, 6H), 6.39 (s,1H), 2.39 (s, 3H), 1.29 (s, 9H). UPLC: (254 nm) 100% purity; Rt 3.97min. LC/MS: 533.2 [M+H].

Example 11:1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-2-chloro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(20)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (76 mg; 0.33 mmol; 1.0 eq)and 5-(4-Amino-3-chloro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine(Intermediate 10, 91 mg; 0.33 mmol; 1.0 eq) as a yellow foam (10 mg,5%). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.78 (s, 1H), 8.35 (s,1H), 8.26 (d, J=8.5 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.52 (s, 1H),7.44-7.34 (m, 5H), 6.40 (s, 1H), 2.39 (s, 3H), 1.29 (s, 8H). UPLC: (254nm) 99% purity; Rt 3.93 min. LC/MS: 533.2 [M+H].

Example 12:1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(13)

A mixture of 5-Bromo-thieno[2,3-d]pyrimidin-4-ylamine (100 mg; 0.43mmol; 1.2 eq),1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea(172 mg; 0.36 mmol; 1.0 eq), Pd(dppf)Cl₂.DCM (59 mg; 0.73 mmol; 0.2 eq)and cesium carbonate (260 mg; 0.8 mmol; 2.2 eq) in 1,4-dioxane (3.5 mL)and water (1 mL) was stirred overnight at 100° C. under nitrogenatmosphere. The reaction mixture was then filtered through a celite pad.The filtrate was diluted with EtOAc (50 mL) and washed with 1M NaOH(2×30 mL) and brine (2×30 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated. Purification by Preparative HPLC(column C18 X-Bridge 30×250 mm, 10 um, gradient 30-95 ACN with 0.1%ammonium hydroxide) afforded the title compound as a white powder (41mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.44 (s, 1H), 8.34(s, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.48-7.28 (m, 7H), 6.38 (s, 1H), 2.39(s, 3H), 1.29 (s, 9H). UPLC: (254 nm) 100% purity; Rt 3.63 min. LC/MS:598.3 [M+H].

Example 13:1-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-phenyl]-3-(2-p-tolyl-5-trifluoromethyl-2H-pyrazol-3-yl)-urea(26)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from2-p-Tolyl-5-trifluoromethyl-2H-pyrazol-3-ylamine (56 mg; 0.23 mmol; 1.0eq) and3-(4-Amino-2-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine(Intermediate 2, 60 mg; 0.23 mmol; 1.0 eq) as a white powder (7 mg, 6%).1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.20 (s, 1H), 8.31 (t, J=8.6Hz, 1H), 8.26 (s, 1H), 7.57-7.39 (m, 6H), 6.91 (s, 1H), 3.95 (s, 3H),2.44 (s, 3H). UPLC: (254 nm) 100% purity; Rt 3.72 min. LC/MS: 525.2[M+H].

Example 14:1-[4-(4-Amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-[5-tert-butyl-2-(4-isopropyl-phenyl)-2H-pyrazol-3-yl]-urea(16)

The title compound was obtained following a similar procedure asdescribed for example 9 but starting from3-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl]-1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea(intermediate 13, 200 mg, 0.38 mmol, 1.0 eq) and3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (intermediate 12, 130mg, 0.45 mmol, 1.2 eq) as a white solid (20 mg, 10%). 1H NMR (400 MHz,DMSO-d6): δ 9.22 (s, 1H), 8.48 (s, 1H), 7.74-7.73 (d, J=6 Hz, 1H),7.59-7.51 (m, 4H), 7.44-7.38 (m, 4H), 6.83-6.82 (d, J=6 Hz, 1H), 6.38(s, 1H), 5.74 (s, 2H), 3.94 (s, 3H), 2.98-2.95 (m, 1H), 1.27 (s, 9H),1.25-1.23 (d, J=6.8 Hz, 6H); LC/MS (Column Kinetex 2.6 u XB-C18 100 A,3.0×50 mm, 2.6 um; Water/ACN with 0.05% TFA, Gradient from 5% to 95% in1.2 min, hold 0.55 min; 254 nm): 99% purity; 523 [M+H]. mp: 152-154° C.

Example 15:2-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-N-[5-tert-butyl-2-(4-isopropyl-phenyl)-2H-pyrazol-3-yl]-acetamide(21)

The title compound was obtained following a similar procedure asdescribed for example 9 but starting fromN-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl]-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide(intermediate 14, 65 mg, 0.09 mmol, 1.0 eq) and3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol,1.1 eq) as a white solid (15 mg, 32%). 1H NMR (300 MHz, CDCl₃) δ 8.43(s, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.44-7.34 (m, 3H), 7.24-7.17 (m, 2H),7.09 (m, 2H), 6.64 (s, 1H), 5.40 (s, 2H), 4.12 (s, 3H), 3.78 (s, 2H),2.80 (m, 1H), 1.33 (s, 9H), 1.11 (d, J=6.9 Hz, 6H). LC/MS (ColumnKinetex EVO C18 100 A, 3.0×50 mm, 2.6 um; water with 5 mM NH₄HCO₃/ACNGradient from 10% to 95% in 2.0 min, hold 0.5 min; 254 nm): 100% purity;523.3 [M+H]. mp: 218-219° C.

Example 16:2-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]-N-[5-tert-butyl-2-(4-isopropyl-phenyl)-2H-pyrazol-3-yl]-acetamide(19)

The title compound was obtained following a similar procedure asdescribed for example 9 but starting fromN-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl]-2-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide(300 mg, 0.32 mmol, 1.0 eq) and3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.38 mmol,1.2 eq) as a white solid (30 mg, 17%). 1H NMR (400 MHz, CDCl₃) δ 8.41(s, 1H), 7.54-7.43 (m, 4H), 7.29 (m, 2H), 7.24 (m, 2H), 6.63 (s, 1H),5.81 (s, 2H), 4.12 (s, 3H), 3.77 (s, 2H), 2.89 (m, 1H), 1.33 (s, 9H),1.19 (d, J=6.9 Hz, 6H). LC/MS (Column Kinetex EVO C18 100 A, 3.0×50 mm,2.6 um; water/5 mM NH₄HCO₃/Acetonitrile from 10 to 95%, 254 nm): 100%purity; 541.3 [M+H].

Example 17:1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)-3-[3-(1-hydroxy-2-methylpropan-2-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea(22) Step 1:2-(5-{3-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-phenyl]-ureido}-1-p-tolyl-1H-pyrazol-3-yl)-2-methyl-propylacetate

The title compound was obtained following a similar procedure asdescribed for example 9 but starting from2-[5-([[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]amino)-1-(4-methylphenyl)-1H-pyrazol-3-yl]-2-methylpropylacetate (intermediate 16, 200 mg, 0.35 mmol, 1.00 eq) and3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.36 mmol,1.03 eq) as an off-white solid (15 mg, 7%). 1H NMR (400 MHz, DMSO-d6) δ9.25 (s, 1H), 8.79 (s, 1H), 8.29-8.27 (d, 1H), 8.24 (s, 1H), 7.66-7.65(d, 1H), 7.57-7.54 (dd, 1H), 7.41-7.39 (d, 2H), 7.36-7.34 (d, 2H), 6.43(s, 1H), 4.09 (s, 2H), 3.92 (s, 3H), 2.37 (s, 3H), 2.01 (s, 3H), 1.27(s, 6H). LC/MS (Column Kinetex EVO C18 100 A, 3.0×50 mm, 2.6 um; waterwith 5 mM NH₄HCO₃/ACN Gradient from 10% to 95% in 2.0 min, hold 0.5 min;254 nm): 96% purity; 588.2 [M+H]. mp: 126-128° C.

Step 2:1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)-3-[3-(1-hydroxy-2-methylpropan-2-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea

A solution of2-(5-[[(4-[4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-chlorophenyl)carbamoyl]amino]-1-(4-methylphenyl)-1H-pyrazol-3-yl)-2-methylpropylacetate (100 mg, 0.15 mmol, 1.00 eq) and potassium carbonate (33 mg,0.23 mmol, 1.5 eq) in MeOH (5 mL) was stirred for 2 h at RT. Solvent wasremoved under reduced pressure. Purification by Preparative HPLC (ColumnGemini-NX C18 AXAI Packed, 21.2×150 mm, Sum, Water with 0.05% NH₄OH/ACNfrom 33% to 46% in 8 min) afforded the title compound as a white solid(10 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.78 (s, 1H),8.30 (d, J=8.6 Hz, 1H), 8.26 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.57 (dd,J=8.6, 2.1 Hz, 1H), 7.45-7.33 (m, 4H), 6.91 (s, 1H), 6.39 (s, 1H), 4.62(t, J=5.5 Hz, 1H), 3.94 (s, 3H), 3.44 (d, J=5.1 Hz, 2H), 2.38 (s, 3H),1.22 (s, 6H). LC/MS (Column Kinetex EVO C18 100 A, 3.0×50 mm, 2.6 um;water with 5 mM NH₄HCO₃/ACN Gradient from 10% to 95% in 2.0 min, hold0.5 min; 254 nm): 98% (purity); 546.3 [M+H], mp: 192-194° C.

Example 18:1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)-3-[3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea(24)

The title compound was obtained following a similar procedure asdescribed for example 9 but starting from1-[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea(intermediate 18, 120 mg, 0.18 mmol, 1.0 eq) and3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate 17, 68mg, 0.22 mmol, 1.2 eq) as a white solid (10 mg, 10%). 1H NMR (300 MHz,DMSO-d6) δ 9.32 (s, 1H), 8.83 (s, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.26 (s,1H), 7.68 (d, J=2.0 Hz, 1H), 7.58 (dd, J=8.5, 2.0 Hz, 1H), 7.41 (d, 4H),6.93 (s, 1H), 6.54 (s, 1H), 4.85 (d, J=5.3 Hz, 2H), 4.47 (d, J=5.4 Hz,2H), 3.94 (s, 3H), 2.40 (s, 3H), 1.67 (s, 3H). LC/MS (Column Shim-packXR-ODS, 3.0×50 mm, 2.2 um; Water/CAN with 0.05% TFA, Gradient from 5 to100% in 2.2 min, hold 1.0 min; 254 nm): 95% purity; 544.2 [M+H]. mp:170-172° C.

Example 19:2-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-hydroxy-acetamide(17)

The title compound was obtained following a similar procedure asdescribed for example 9 but starting fromN-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-hydroxy-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide(intermediate 19, 40 mg, 0.07 mmol, 1.0 eq) and3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (22 mg, 0.07 mmol,1.10 eq) as a white solid (21 mg, 62%). 1H NMR (300 MHz, DMSO-d6) δ 9.87(s, 1H), 8.28 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H),7.34-7.24 (m, 2H), 7.19 (d, J=8.3 Hz, 2H), 6.66-6.57 (m, 1H), 6.30 (s,1H), 5.18-5.12 (m, 1H), 3.97 (s, 3H), 2.30 (s, 3H), 1.26 (s, 9H). LC/MS(Column Shim-pack XR-ODS, 3.0×50 mm, 2.2 um; Water/ACN with 0.05% TFAGradient from 5% to 100% in 2.2 min, hold 1.0 min; 254 nm): 99% purity;511.3 [M+H]. mp: 260-262° C.

Example 20:2-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]-N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-oxo-acetamide(7)

A solution of2-(4-[4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-hydroxyacetamide(50 mg, 0.09 mmol, 1.0 eq) and IBX (52 mg, 0.18 mmol, 2.0 eq) in DMSO (1mL) was stirred for 4 h at 20° C. Purification by Prep-HPLC (ColumnGemini-NX C18 AXAI Packed, 21.2×150 mm, Sum, Water with 0.05% NH₄OH/ACNgradient from 50% to 62% in 8 min) afforded the title compound as ayellow solid (20 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H),8.30 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 7.40 (d,J=8.4 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 7.05 (s, 2H), 6.53 (s, 1H), 3.99(s, 3H), 2.37 (s, 3H), 1.32 (s, 9H). LC/MS (Column Phenomenex Gemini-NXC18 3.0×50 mm, 3.0 um; Water with 6.5 mM NH₄HCO₃/ACN, Gradient from 5%to 95% in 2.2 min, hold 1.0 min; 254 nm): 99% purity; 509.1 [M+H].

Example 21:1-(4-{4-aminothieno[2,3-d]pyrimidin-5-yl}-2-chlorophenyl)-3-[3-(1-hydroxy-2-methylpropan-2-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea(27) Step 1:2-(5-{3-[4-(4-amino-thieno[2,3-d]pyrimidin-5-yl)-2-chloro-phenyl]-ureido}-1-p-tolyl-1H-pyrazol-3-yl)-2-methyl-propylacetate

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from2-(5-amino-1-p-tolyl-1H-pyrazol-3-yl)-2-methyl-propyl ester (prepared asdescribed in Journal of Medicinal Chemistry, 46(22), 4676-4686; 2003;208 mg; 0.72 mmol; 1.0 eq) and5-(4-Amino-3-chloro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine(intermediate 10; 200 mg; 0.72 mmol; 1.0 eq) as a white solid (40 mg,9%). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.78 (s, 1H), 8.35 (s,1H), 8.25 (d, J=8.6 Hz, 1H), 7.63-7.27 (m, 7H), 6.45 (s, 1H), 4.12 (s,2H), 2.39 (s, 3H), 2.04 (s, 3H), 1.29 (s, 6H). UPLC/MS 590.3 [M+H].

Step 2:1-(4-{4-aminothieno[2,3-d]pyrimidin-5-yl}-2-chlorophenyl)-3-[3-(1-hydroxy-2-methylpropan-2-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea

A solution of2-(5-{3-[4-(4-amino-thieno[2,3-d]pyrimidin-5-yl)-2-chloro-phenyl]-ureido}-1-p-tolyl-1H-pyrazol-3-yl)-2-methyl-propylester (40 mg; 0.07 mmol; 1.0 eq) and K₂CO₃ (28 mg, 0.20 mmol; 3 eq) inMeOH (2 mL) was stirred for 1 h at RT. The reaction mixture was thendiluted with a saturated solution of sodium bicarbonate (2 mL) andextracted with EtOAc (3×3 mL). Combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated.Purification by flash chromatography on silica (EP: EtOAc; gradient from100:0 to 0:100) afforded the title compound as a white solid (27 mg,73%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.77 (s, 1H), 8.35 (s,1H), 8.26 (d, J=8.5 Hz, 1H), 7.57 (d, J=2.1 Hz, 1H), 7.52 (s, 1H),7.47-7.33 (m, 4H), 6.39 (s, 1H), 4.59 (t, J=5.6 Hz, 1H), 3.45 (d, J=5.5Hz, 2H), 2.39 (s, 3H), 1.23 (s, 6H). UPLC: (254 nm) 100% purity; Rt 3.13min. LC/MS: 551.0 [M+H].

Example 22:1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-2-chloro-phenyl]-3-[5-(cyano-dimethyl-methyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea(25)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from2-(5-Amino-1-p-tolyl-1H-pyrazol-3-yl)-2-methyl-propionitrile(intermediate 21; 43 mg; 0.18 mmol; 1.0 eq) and5-(4-Amino-3-chloro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine(intermediate 10; 50 mg; 0.18 mmol; 1.0 eq) as a white solid (18 mg,19%). 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.86 (s, 1H), 8.35 (s,1H), 8.26 (d, J=8.5 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.53 (s, 1H),7.48-7.38 (m, 5H), 6.62 (s, 1H), 5.76 (s, 1H), 2.42 (s, 3H), 1.71 (s,6H). UPLC: (254 nm) 99% purity; Rt 3.69 min. UPLC/MS: 543.0 [M+H].

Example 23:1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-2-chloro-3-fluoro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(23)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine (24 mg; 0.11 mmol; 1.0 eq)and5-(4-Amino-3-chloro-2-fluoro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine(intermediate 23; 31 mg; 0.11 mmol; 1.0 eq) as a white solid (3 mg, 5%).1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.90 (s, 1H), 8.35 (s, 1H),8.13 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.48-7.28 (m, 4H), 6.41 (s, 1H),2.40 (s, 3H), 1.29 (s, 9H). UPLC: (254 nm) 100% purity; Rt 4.02 min.UPLC/MS: 550.0 [M+H].

Example 24:1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-2-chloro-phenyl]-3-[2-p-tolyl-5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-2H-pyrazol-3-yl]-urea(18)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from2-p-Tolyl-5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-2H-pyrazol-3-ylamine(51 mg; 0.18 mmol; 1.0 eq) and5-(4-Amino-3-chloro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine(intermediate 10; 50 mg; 0.18 mmol; 1.0 eq) as a white solid (14 mg,13%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.83 (s, 1H), 8.35 (s,1H), 8.26 (d, J=8.6 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.53 (s, 1H), 7.46(d, J=8.1 Hz, 2H), 7.42-7.37 (m, 3H), 6.59 (s, 1H), 2.41 (s, 3H), 1.53(s, 6H). UPLC: (254 nm) 100% purity; Rt 4.28 min. LC/MS: 586.0 [M+H].

Example 25:1-[4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-cyclohex-3-enyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(1)

A solution of 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (94 mg,0.37 mmol, 1.0 eq) and DIEA (201 mg, 1.48 mmol, 4.0 eq) in DCM (2 mL)was added dropwise to a solution of triphosgene (69 mg, 0.22 mmol, 0.60eq) in DCM (2 mL) maintained at 0° C. and under nitrogen atmosphere. Thereaction mixture was stirred for 2 h at 0° C. before the addition of asolution of5-(4-aminocyclohex-1-en-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(intermediate 24; 100 mg, 0.37 mmol, 1.0 eq) in DMF (2 mL). Theresulting reaction mixture was stirred for 4 h at RT and diluted withDCM (10 mL). It was washed with a saturated solution of NH₄Cl (2×10 mL)and brine (1×10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by Prep-HPLC (Column XBridge BEH130 Prep C18OBD Column, 19×150 mm, Sum; Water with 0.05% NH₄OH/CAN, 36% ACN for 17min) afforded the title compound as a white solid (16 mg, 8%). 1H NMR(300 MHz, DMSO-d6) δ 8.09-8.04 (m, 2H), 7.36-7.29 (m, 4H), 7.18 (s, 1H),6.68-6.65 (m, 1H), 6.29-6.25 (m, 3H), 5.62 (s, 1H), 3.85-3.81 (m, 1H),3.66 (s, 3H), 2.49-2.43 (m, 3H), 2.36 (s, 3H), 2.08-2.01 (m, 1H),1.91-1.88 (m, 1H), 1.68-1.62 (m, 1H), 1.25 (s, 9H). LC/MS (ColumnAscentis Express C18, 3.0×50 mm, 2.7 um; Water/ACN with 0.05% TFA,Gradient 5% to 100% in 1.2 min, hold 0.5 min; 254 nm): 96% purity; 499.3[M+H]. mp: 145-147° C.

Example 26:1-[4-(4-Amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-fluoro-phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea(3)

The title compound was obtained following a similar procedure asdescribed for example 9 but starting from3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea(intermediate 25, 150 mg, 0.27 mmol, 1.0 eq) and3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (intermediate 12, 894mg, 3.1 mmol, 11.3 eq) as a white solid (10 mg, 7%). 1H NMR (300 MHz,DMSO-d6) δ 9.09 (s, 1H), 8.86 (s, 1H), 8.27 (t, J=8.4 Hz, 1H), 7.73 (d,J=6.1 Hz, 1H), 7.49-7.27 (m, 6H), 6.82 (d, J=6.0 Hz, 1H), 6.38 (s, 1H),5.79 (s, 2H), 3.93 (s, 3H), 2.36 (s, 3H), 2.04 (s, 1H), 1.25 (s, 10H).LC/MS (Column Poroshell HPH-C18, 3.0×50 mm, 2.7 um; Water with 5 mMNH₄HCO₃/ACN, Gradient from 10% to 95% in 2.2 min, hold 1.0 min; 254 nm):100% purity; 513.0 [M+H].

Example 27:3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[(1s,4s)-4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl]urea(5)

A solution of1-(4-[4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl]cyclohex-3-en-1-yl)-3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea(60 mg, 0.11 mmol, 1.0 eq) in MeOH (5 mL) was hydrogenated (1 atm) for48 h in presence of Palladium on carbon (20 mg). The reaction mixturewas then filtrated through a Celite pad and concentrated under reducedpressure. Purification by Prep-HPLC (Column X-Bridge Prep C18 OBDColumn, 19×150 mm, 5 um, Water with 10 mM NH₄CO₃+0.1% NH₄OH/ACN,gradient from 38.0% to 40.0% in 20 min) afforded the title compound as awhite solid (9.9 mg, 17%). 1H NMR (300 MHz, DMSO-d6): δ 8.05-8.03 (m,2H), 7.36-7.30 (m, 4H), 6.83 (s, 1H), 6.74-6.71 (m, 1H), 6.43 (s, 2H),6.29 (s, 1H), 3.86 (m, 1H), 3.58 (s, 3H), 2.97 (s, 1H), 2.32 (s, 3H),2.01-1.56 (m, 6H), 1.40 (m, 2H), 1.21 (s, 9H). LC/MS (Column Shim-packXR-ODS, 3.0×50 mm, 2.2 um; Water/CAN with 0.05% TFA, Gradient from 5% to100% in 2.0 min, hold 0.7 min; 254 nm): 95% purity; 501.3 [M+H]. mp:228-230° C.

Example 28:1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)-3-[3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl]urea(28)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from4-[5-Amino-3-(1,1-dimethylethyl)-1H-pyrazol-1-yl]benzonitrile as a beigesolid. 1H NMR (400 MH DMSO-d6) δ 1.30 (s, 9H), 3.99 (s, 3H), 5.76 (s,1H), 7.55 (d, J=8.6 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.77 (d, J=7.2 Hz,2H), 7.98 (d, J=7.2 Hz, 2H), 8.20 (d, =8.5 Hz, 111), 8.39 (s, 1H), 8.80(s, 1H), 9.43 (s, 1H). HPLC (Atlantis dC18, 254×4.6 mm, Sum, gradientTFA 0.1% in water/ACN 10% to 100% in 15 min, 254 nm) 98.0% purity; Rt12.7 min. LC/MS (ESI−): 539.0 [M−H].

Example 29:1-[4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chloro-phenyl]-3-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-urea(29)

The title compound was obtained following a similar procedure asdescribed for example 1 but starting from5-tert-Butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-ylamine as abeige solid. 1H NMR (400 MH, DMSO-d6) δ 1.28 (s, 9H), 2.29 (s, 3H), 3.98(s, 3H), 4.5 (brs, 2H), 6.41 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.37 (d,J=11.8 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.69 (d,J=1.4 Hz, 1H), 8.29 (d, J=8.6 Hz, 1H), 8.80 (s, 1H), 9.28 (s, 1H). HPLC:(Atlantis dC18, 254×4.6 mm, 5 um, gradient TFA 0.1% in water/ACN 10% to100% in 15 min, 254 nm) 97.3% purity; Rt 13.3 min. LC/MS (ESI−): 546.0[M−H].

Example 30: Enzymatic and Cellular Assays

IRAK4 Enzymatic Assay:

IRAK4 is a human purified recombinant enzyme (His-TEV-IRAK4 (1-460)). Inthis assay, IRAK4 hydrolysed ATP, autophosphorylated and phosphorylateda Serine/Threonine generic peptidic substrate (STK: 61ST1BLC from CisBioInternational). Measurement of IRAK-4 inhibition was performed in384-well format based on a luminescence assay (ADP-Glo™ Kinase Assayfrom Promega). Purified human recombinant IRAK4 (0.3 μg/ml) and serialdiluted compounds in DMSO (range of concentration from 10 μM to 0.5 nM)or controls (1% DMSO) were incubated for 15 minutes at RT in assaybuffer containing 50 mM Hepes pH 7.0, Fatty acid-free BSA 0.1%,Dithiothreitol (DTT) 2 mM, MgCl2 10 mM, EGTA 0.5 mM, Triton X-100 0.01%,MnCl2 5 mM. The kinase reaction was then initiated by the addition ofATP (2 μM) and the peptidic substrate STK1-biotin peptide (300 nM).After 2 hours of incubation at RT, the reaction was stopped and theunconsumed ATP depleted by the addition of ADP-Glo™ Reagent according tosupplier instructions. After 40 minutes of incubation at RT, the KinaseDetection Reagent was then added to the assay plate according tosupplier instructions. After 20 minutes of incubation at RT, theluminescence signal was measured with a plate-reading luminometer(PerkinElmer Envision or equivalent reader).

IRAK1 Enzymatic Assay:

IRAK1 is a human purified recombinant enzyme (His-TEV-IRAK1 (194-712)).In this assay, IRAK1 hydrolysed ATP and autophosphorylated. Measurementof IRAK-1 inhibition was performed in 384-well format based onluminescence assay (ADP-Glo™ Kinase Assay from Promega). Purified humanrecombinant IRAK1 (0.3 μg/ml) and serial diluted compounds in DMSO(range of concentration from 10 μM to 0.5 nM) or controls (1% DMSO) wereincubated for 15 minutes at RT in assay buffer containing 50 mM Hepes pH7.0, Fatty acid-free BSA 0.1%, Dithiothreitol (DTT) 2 mM, MgCl2 10 mM,EGTA 0.5 mM, Triton X-100 0.01%. The kinase reaction was then initiatedby the addition of ATP at a concentration of 1 μM. After 2 hours ofincubation at RT, the reaction was stopped and the unconsumed ATPdepleted by the addition of ADP-Glo™ Reagent according to supplierinstructions. After 40 minutes of incubation at RT, the Kinase DetectionReagent was then added to the assay plate according to supplierinstructions. After 20 minutes of incubation at RT, the luminescencesignal was measured with a luminometer (PerkinElmer Envision orequivalent reader).

TLR7 Induced IL-6 in Human PBMC's

Human PBMC assay was used as one of the functional assays to monitor theactivity of IRAK1 and IRAK4 small molecule inhibitors on TLR7 inducedIL-6 secretion in human mononuclear cells (PBMC's). Human PBMCs wereprepared from buffy coats (whole blood enriched with leukocytes andplatelets) obtained from healthy volunteers used either fresh or frozenwere plated in assay media (RPMI+2% P/S/L-glu+10% HI-FBS) andpre-treated with compounds in DMSO/media (range of concentrations from25 uM to 0.4 nM) or controls (0.25% DMSO) for 30 minutes at 37° C. inassay media. Following pre-treatment with IRAK1 and IRAK4 inhibitors,PBMC's were stimulated with TLR7 specific ligand (2 uM) overnight (16-18hrs) at 37° C. After incubation supernatant was transferred to 384 wellPE AlphaPlate-384 and IL-6 was quantified using Perkin Elmer IL-6 AlphaLISA kit (AL223C). Plates were read on an Envision® plate reader withAlpha Technology®.

Results are given in the following table.

Example Compound IRAK1 IRAK4 PBMC 1 15 **** *** **** 2 2 **** **** ****3 11 **** *** **** 4 6 **** **** **** 5 4 **** **** **** 6 12 **** ******* 7 9 **** **** **** 8 8 **** **** **** 9 10 **** **** **** 10 14**** *** **** 11 20 **** ** **** 12 13 **** *** **** 13 26 *** * *** 1416 **** *** **** 15 21 **** ** ** 16 19 **** *** ** 17 22 **** ** ****18 24 **** ** *** 19 17 **** *** *** 20 7 **** **** ** 21 27 *** * * 2225 *** ** * 23 23 **** ** **** 24 18 **** *** **** 25 1 **** **** NT 263 **** *** **** 27 5 *** ** NT 28 28 **** *** NT 29 29 **** *** NT *IC₅₀ >5 μM ** IC₅₀ ranges from 1 μM-5 μM *** IC₅₀ ranges from 100 nM-1.0μM **** IC₅₀ <100 nM NT Not Tested

Example 31: Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 31of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, transferred into injection vials, is lyophilized understerile conditions and is sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention is melted with 100 g of soy lecithin and 1400 g ofcocoa butter, is poured into moulds and is allowed to cool. Eachsuppository contains 20 mg of active ingredient.

(C) Solution: A solution is prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbidistilled water. The pH is adjusted to 6.8, and the solution is madeup to 1 l and sterilized by irradiation. This solution could be used inthe form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionis mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate is pressed to give tablets in aconventional manner in such a way that each tablet contains 10 mg ofactive ingredient.

(F) Coated tablets: Tablets are pressed analogously to Example E andsubsequently are coated in a conventional manner with a coating ofsucrose, potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionare introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water is sterile filtered,transferred into ampoules, is lyophilized under sterile conditions andis sealed under sterile conditions. Each ampoule contains 10 mg ofactive ingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention are dissolved in 10 l of isotonic NaCl solution, and thesolution is transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14mg.

While a number of embodiments of this invention are described herein, itis apparent that the basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: A′ is C═O, C(R)₂or NR; L is a divalent group selected from C₆₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted; X is CR orN; Y is NR or S; Z is CR or N; R¹ is C₆₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted; R² is —R,halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R,—C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; each R isindependently hydrogen, C₁₋₆ aliphatic, C₆₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted; or two Rgroups on the same atom are taken together with the atom to which theyare attached to form a C₆₋₁₀ aryl, a 3-8 membered saturated or partiallyunsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of whichis optionally substituted.
 2. The compound of claim 1, wherein A′ isC═O, CH₂, CHOH, or NH.
 3. The compound of claim 1, wherein L is adivalent group selected from phenyl, cyclopentyl, cyclohexyl,cyclohexenyl, cycloheptyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, isoxazolyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; -1,2,5oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,thiazolyl, thienyl, thiophenyl, oxetanyl, and azetidinyl, each of whichis optionally substituted.
 4. The compound of claim 3, wherein L is adivalent group selected from


5. The compound of claim 1, wherein R¹ is C₆₋₁₀ aryl.
 6. The compound ofclaim 5, wherein R¹ is


7. The compound of claim 1, wherein R¹ is C₁₋₆ aliphatic or 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.
 8. The compound of claim 7, wherein R¹ ismethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl, straightchain or branched pentyl, or straight chain or branched hexyl, or R² isa 4 membered heterocylic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.
 9. The compound of claim 8,wherein R¹ is —CF₃,


10. The compound of claim 1, of formula I-a,

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1, of formula I-c,

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, of formula I-e,

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, of formula I-h,

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, selected from

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 1, and a pharmaceuticallyacceptable adjuvant, carrier, or vehicle.
 16. A method for inhibitingIRAK, or a mutant thereof, activity in a patient or in a biologicalsample, comprising the step of administering to said patient orcontacting said biological sample with a compound of claim 1 or aphysiologically acceptable salt thereof.
 17. A method for treating anIRAK-mediated disorder in a patient in need thereof, comprising the stepof administering to said patient a compound of claim
 1. 18. The methodof claim 17, wherein the disorder is selected from Rheumatoid Arthritis,Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupusnephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis,Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes,Inflammatory Bowel Disease (Cronh's Disease and Ulcerative Colitis),Hyperimmunoglobulinemia D and periodic fever syndrome,Cryopyrin-associated periodic syndromes, Schnitzler's syndrome, Systemicjuvenile idiopathic arthritis, Adult's onset Still's disease, Gout,Pseudogout, SAPHO syndrome, Castleman's disease, andometriosis; Sepsis,Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1Receptor Antagonist), Alzheimer's disease, Parkinson's disease, andCancer.
 19. A method for treating cancer in a subject, comprising thestep of administering to said subject a compound of claim 1 or aphysiologically acceptable salt thereof.
 20. The method of claim 18,wherein the disorder is selected from Rheumatoid Arthritis, SystemicLupus Erythematosus, Lupus nephritis, and Multiple Sclerosis.